CN110944665B - 用于预防或治疗肺癌的amhrii结合化合物 - Google Patents
用于预防或治疗肺癌的amhrii结合化合物 Download PDFInfo
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- CN110944665B CN110944665B CN201880040211.4A CN201880040211A CN110944665B CN 110944665 B CN110944665 B CN 110944665B CN 201880040211 A CN201880040211 A CN 201880040211A CN 110944665 B CN110944665 B CN 110944665B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57423—Specifically defined cancers of lung
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Endocrinology (AREA)
- Neurology (AREA)
- Zoology (AREA)
- Urology & Nephrology (AREA)
- Developmental Biology & Embryology (AREA)
- Virology (AREA)
- Microbiology (AREA)
- Food Science & Technology (AREA)
- General Physics & Mathematics (AREA)
- Oncology (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Pathology (AREA)
- Hospice & Palliative Care (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17305446.1 | 2017-04-14 | ||
| EP17305446 | 2017-04-14 | ||
| PCT/EP2018/059553 WO2018189381A1 (en) | 2017-04-14 | 2018-04-13 | Amhrii-binding compounds for preventing or treating lung cancers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110944665A CN110944665A (zh) | 2020-03-31 |
| CN110944665B true CN110944665B (zh) | 2024-04-19 |
Family
ID=58672546
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880040211.4A Active CN110944665B (zh) | 2017-04-14 | 2018-04-13 | 用于预防或治疗肺癌的amhrii结合化合物 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20230227566A1 (enExample) |
| EP (1) | EP3609919A1 (enExample) |
| JP (1) | JP7289420B6 (enExample) |
| KR (2) | KR20250017758A (enExample) |
| CN (1) | CN110944665B (enExample) |
| BR (1) | BR112019021495A8 (enExample) |
| CA (1) | CA3058541A1 (enExample) |
| MX (2) | MX2019012136A (enExample) |
| WO (1) | WO2018189381A1 (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110891970B (zh) * | 2017-04-14 | 2024-05-10 | 埃克塞里艾克西斯公司 | 用于预防或治疗癌症的amhrii结合化合物 |
| WO2020160217A1 (en) * | 2019-02-01 | 2020-08-06 | Seattle Children's Hospital (dba Seattle Children's Research Institute) | Microenvironment sensors to regulate engineered gene expression |
| WO2020243679A1 (en) * | 2019-05-31 | 2020-12-03 | Detti Laura | Anti-mullerian hormone receptor binding peptides |
| US20220290151A1 (en) * | 2019-09-27 | 2022-09-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of müllerian inhibiting substance inhibitors for treating cancer |
| US20230078601A1 (en) * | 2020-01-31 | 2023-03-16 | The Cleveland Clinic Foundation | Anti-mullerian hormone receptor 2 antibodies and methods of use |
| JP2025506702A (ja) * | 2022-02-16 | 2025-03-13 | ザ クリーブランド クリニック ファウンデーション | Amhr2-edがんワクチン製剤 |
| WO2025149667A1 (en) | 2024-01-12 | 2025-07-17 | Pheon Therapeutics Ltd | Antibody drug conjugates and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101573382A (zh) * | 2006-11-02 | 2009-11-04 | 法国国家健康医学研究院 | 针对人抗苗勒激素ⅱ型受体(amhr-ⅱ)的单克隆抗体 |
| WO2017025458A1 (en) * | 2015-08-07 | 2017-02-16 | Gamamabs Pharma | Antibodies, antibody drug conjugates and methods of use |
Family Cites Families (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
| GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
| US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
| GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
| US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
| DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
| GB8928874D0 (en) | 1989-12-21 | 1990-02-28 | Celltech Ltd | Humanised antibodies |
| US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
| US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
| US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
| US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
| KR100272077B1 (ko) | 1990-08-29 | 2000-11-15 | 젠팜인터내셔날,인코포레이티드 | 이종 항체를 생산할 수 있는 전이유전자를 가진 인간이외의 동물 |
| WO1992009690A2 (en) | 1990-12-03 | 1992-06-11 | Genentech, Inc. | Enrichment method for variant proteins with altered binding properties |
| DE69233482T2 (de) | 1991-05-17 | 2006-01-12 | Merck & Co., Inc. | Verfahren zur Verminderung der Immunogenität der variablen Antikörperdomänen |
| US5565332A (en) | 1991-09-23 | 1996-10-15 | Medical Research Council | Production of chimeric antibodies - a combinatorial approach |
| AU3178993A (en) | 1991-11-25 | 1993-06-28 | Enzon, Inc. | Multivalent antigen-binding proteins |
| US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
| EP0770628B9 (en) | 1994-07-13 | 2007-02-28 | Chugai Seiyaku Kabushiki Kaisha | Reconstituted human antibody against human interleukin-8 |
| US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
| US6242195B1 (en) | 1998-04-02 | 2001-06-05 | Genentech, Inc. | Methods for determining binding of an analyte to a receptor |
| DE69937291T2 (de) | 1998-04-02 | 2008-07-10 | Genentech, Inc., South San Francisco | Antikörpervarianten und fragmente davon |
| US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
| BR0008758A (pt) | 1999-01-15 | 2001-12-04 | Genentech Inc | Variantes de polipeptìdeos parentais com funçãoefetora alterada, polipeptìdeos, composição ácidonucleico isolado, vetor, célula hospedeira,método para produzir uma variante depolipeptìdeo, método para o tratamento de umadesordem em mamìferos e método para produziruma região fc variante |
| WO2005005615A2 (en) * | 2003-07-08 | 2005-01-20 | Fox Chase Cancer Center | Anti-mullerian inhibiting substance type ii receptor (misiir) immunoconjugates to detect and treat cancer |
| WO2008116161A2 (en) * | 2007-03-22 | 2008-09-25 | The General Hospital Corporation | Pyrazoloanthrone and derivatives thereof for the treatment of cancer expressing 'mullerian inhibiting substance' type ii receptor (misrii) and of excess androgen states |
| FR2959994B1 (fr) | 2010-05-12 | 2012-08-24 | Lfb Biotechnologies | Nouveaux anticorps humanises 12g4 mutes et leurs fragments diriges contre le recepteur humain de l'hormone anti-mullerienne de type ii |
| WO2012166712A1 (en) * | 2011-05-27 | 2012-12-06 | Fox Chase Cancer Center | Rationally-designed anti-mullerian inhibiting substance type ii receptor antibodies |
| FR2984750B1 (fr) * | 2011-12-23 | 2014-01-10 | Lfb Biotechnologies | Nouvelles compositions pharmaceutiques comprenant un anticorps liant le recepteur humain de l'hormone anti-mullerienne de type ii |
| WO2018148649A1 (en) * | 2017-02-10 | 2018-08-16 | The Institute For Cancer Research D/B/A | Chimera of bone morphogenic protein 2 and the müllerian-inhibiting substance type ii receptor binding region of mullerian-inhibiting substance |
| CN110891970B (zh) * | 2017-04-14 | 2024-05-10 | 埃克塞里艾克西斯公司 | 用于预防或治疗癌症的amhrii结合化合物 |
-
2018
- 2018-04-13 BR BR112019021495A patent/BR112019021495A8/pt unknown
- 2018-04-13 WO PCT/EP2018/059553 patent/WO2018189381A1/en not_active Ceased
- 2018-04-13 MX MX2019012136A patent/MX2019012136A/es unknown
- 2018-04-13 EP EP18718420.5A patent/EP3609919A1/en active Pending
- 2018-04-13 KR KR1020257001888A patent/KR20250017758A/ko active Pending
- 2018-04-13 KR KR1020197033360A patent/KR102759138B1/ko active Active
- 2018-04-13 JP JP2019555941A patent/JP7289420B6/ja active Active
- 2018-04-13 US US16/605,053 patent/US20230227566A1/en not_active Abandoned
- 2018-04-13 CA CA3058541A patent/CA3058541A1/en active Pending
- 2018-04-13 CN CN201880040211.4A patent/CN110944665B/zh active Active
-
2019
- 2019-10-09 MX MX2024003228A patent/MX2024003228A/es unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101573382A (zh) * | 2006-11-02 | 2009-11-04 | 法国国家健康医学研究院 | 针对人抗苗勒激素ⅱ型受体(amhr-ⅱ)的单克隆抗体 |
| WO2017025458A1 (en) * | 2015-08-07 | 2017-02-16 | Gamamabs Pharma | Antibodies, antibody drug conjugates and methods of use |
Non-Patent Citations (2)
| Title |
|---|
| "Anti-Mullerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer";Tim N. Beck 等;《Cell Reports》;第16卷;第662页第3段-第665页第1段 * |
| "抗苗勒氏管激素及其Ⅱ型受体的基因多态性与多囊卵巢综合征发病的关系";李健 等;《中国妇产科临床杂志》;第9卷(第3期);第206-210页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| BR112019021495A8 (pt) | 2023-05-02 |
| RU2019131542A (ru) | 2021-05-14 |
| RU2019131542A3 (enExample) | 2021-08-18 |
| KR20250017758A (ko) | 2025-02-04 |
| KR20200014277A (ko) | 2020-02-10 |
| BR112019021495A2 (pt) | 2020-05-12 |
| US20230227566A1 (en) | 2023-07-20 |
| MX2024003228A (es) | 2024-07-10 |
| JP2020516655A (ja) | 2020-06-11 |
| WO2018189381A1 (en) | 2018-10-18 |
| JP7289420B2 (ja) | 2023-06-12 |
| CA3058541A1 (en) | 2018-10-18 |
| KR102759138B1 (ko) | 2025-01-23 |
| EP3609919A1 (en) | 2020-02-19 |
| JP7289420B6 (ja) | 2023-06-30 |
| MX2019012136A (es) | 2020-07-20 |
| CN110944665A (zh) | 2020-03-31 |
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